Chemoradiotherapy

Radiotherapy is given to the tumor and inguinal nodes. Radiation therapy alone may lead to a 5-year survival rate in excess of 70%. Several retrospective series have previously reported excellent outcomes for patients with T1, N0, and M0 disease with radiation alone.


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Following the publication of the results of the national anal cancer ACT II trial,29 radiotherapy accompanied by administration of mitomycin and 5-fluorouracil (5-FU) and is now regarded as the standard treatment for anal cancer. The most commonly used regimen is described in the ACT II study: 50.4 Gy in 28 fractions in two phases compared with American and European centers, where the prescription dose can range from 54 to 59 Gy in varying schedules.30,31

Mitomycin is a potent DNA crosslinker. A single crosslink per genome has been shown to be effective in killing bacteria. This is achieved by reductive activation followed by two N-alkylation’s thus preventing the formation of DNA and leading to cell death.31 5-FU is a thymidylate synthase inhibitor, which interrupts the action of this enzyme and blocks the synthesis of the pyrimidine thymidine, which is a nucleoside required for DNA replication.32

There is accumulating retrospective data from recent studies showing the effectiveness of chemotherapy concurrent with intense modulated radiotherapy that have shown actuarial colostomy-free survival with local control rates of 83.7% and 83.9%, as well as a favorable toxicity profile.33

Early and late chemoradiation toxicities

Complications of chemoradiation therapy for SCC of the anus can be categorized into early and late toxicity. About 60–90% of sphincter preservation preserves quality of life (QOL), although this is not well addressed in the literature. Acute grade 3–4 toxicities occur, mainly consisting of skin reactions, diarrhea, and those that are caused by chemotherapy, ie, nausea, vomiting, mucositis, neutropenia, and infection.

Late complications are not insignificant and can greatly impinge upon patient QOL. These symptoms include chronic diarrhea, dysuria, chronic pelvic pain, fractures, and sexual dysfunction. Overall, complications of anal canal occur in 15–13% of patients and include anal ulcers, anal stenosis and necrosis, fistulae, and anal incontinence.34

Surgery

The indications for surgery are listed below:

  1. Persisting tumor after chemoradiotherapy,
  2. Recurrent tumor after previous radiotherapy, and
  3. Small T1 anal margin tumors without sphincter involvement.

The standard salvage therapy for these former two groups of patients, following chemoradiotherapy, has been abdominoperineal resection (APR). This originally was described by Miles as the resection of the rectum and anus including the sphincter complex. It involves the five abdominal mobilizations of the rectum before the dissection is completed via a perineal approach.

This replicates the “modern” extended extra levator approach, which achieves wider excision and removes more tissue around low rectal tumors, including the ischiorectal fat, resulting in a significant improvement in clear margins. The vagina may need to be excised en bloc when involved, and a plastic surgeon will be required to close large defects in flaps such as the vertical rectus abdominis myocutaneous and the inferior gluteal artery perforator.35

APR can achieve local control in 50–60% of patients, provided that a curative resection can be obtained. In cases involving inguinal lymph nodes, a radical groin dissection should be considered. The European Society of Medical Oncology suggests that local excision can be considered for small well-differentiated carcinomas of the anal margin; ie, <2 cm in diameter, without any evidence of nodal spread.4,36

Studies have described preoperative mapping before excision; however, this may not prevent recurrence. The API is different from the APR for low rectal cancers and sometimes necessitates en block resection of adjacent organs; ie, sometimes a posterior or total pelvic extenuation is required.

Surgery for T1 lesions remains uncertain primarily because of the inability to achieve ideal characteristics in all patients. Specifically, the relatively high degree of failure in achieving appropriate clear margins is disappointing and may account for a significant number of local failures. However, local excision seems to be a viable option in well-selected patients (ie, those with well-differentiated or moderately well-differentiated T1 cancers involving <40% of the circumference, without lymphovascular invasion), particularly when the only other option is APR.34,36,37

Other local treatments

Local treatments, mainly used for the treatment of premalignant lesions such as AIN and Bowen’s disease, have been described for invasive anal cancer for small lesions (<1 cm2) in the perianal or intra-anal regions, including imiquimod 5% cream an immune modulator, which can result in pathological resolution of AIN in HIV-positive MSM on highly active antiretroviral therapy (HAART).38–40

Local application of bichloroacetic or trichloroacetic acid may also be considered, and it is believed to show a response rate of approximately 70%.40,41 Data also suggest that a course of topical 5-FU, photodynamic therapy,42 and CO2laser therapy may be effective.43 However, larger trials need to be conducted in this area to validate their effectiveness.

Lesions that are too large may also undergo high-resolution anoscopy and can be used to visually define areas of involvement for electrocautery ablation.44,45 Limited data are available comparing different treatment modalities in men with high-grade squamous cell intraepithelial neoplasia. There is one randomized trial that studied 156 men who were randomly assigned to imiquimod, topical 5-FU, or electrocautery.

All grades of AIN were included; high-grade intraepithelial neoplasia was present in 57% of cases. Patients with perianal AIN included 17% of the study.45 Among the 148 patients actually treated (modified intent to treat), the complete response rates with imiquimod, 5-FU, and electrocautery were 24%, 17%, and 39%, respectively.